Process of preparing 1,4-diloweralkyl-3-loweralkoxy-carbonyl-2-acetates

ABSTRACT

The compounds are of the class of 5-aroyl-pyrrole alkenoic acids and corresponding acid derivatives thereof useful as antiinflammatory agents and as synthetic intermediates.

United States Patent Carson [4 1 Feb. 11, 1975 PROCESS OF PREPARING 1,4-DILOWERALKYL-3-LOWERALKOXY- CARBONYL-Z-ACETATES [75] Inventor: John Robert Carson, Norristown,

[60] Division of Ser. No. 5,958, Jan. 26, I970, Pat. No. 3,752,826, which is a continuation-in-part of Ser. No. 741,348, July 1, I968, abandoned, which is a continuation-in-part of Ser. No. 656,074, July 26, I967, abandoned.

[52] US. Cl. 260/326.46

511' im. Cl C07d 27/26 [58] Field of Search 260/326.46

[56] References Cited OTHER PUBLICATIONS Hollins, Synthesis of Nitrogen Ring Compounds Primary Examiner-Joseph A. Narcavage Attorney, Agent, or Firm-Salvatore R. Come [57] ABSTRACT The compounds are of the class of 5-aroyl-pyrrole alkenoic acids" and corresponding acid derivatives thereof useful as anti-inflammatory agents and as synthetic intermediates.

5 Claims, No Drawings RQ Es Q BREAKING. l,4-DILOWERALKYL-3-LOWERALKOXY-CARBO- NYYL-Z-ACET-ATES This is a divisional application of my application Ser. No. 5,958, filed Jan. 26, 1970, issued as US. Pat. No. 3,752,826 on Aug. 14, 1973, which in turn is a continuation-in-part application Ser. No. 741,348, filed July 1, 1968, now abandoned, which'in turn is a continuation-in-part application of application Ser. No. 656,074, filed July 26, 1967, now abandoned.

This inventionrelates to novel -aroyl-pyrroles, and, more particularly, to S-aroyl-pyrrole alkanoic acids and the corresponding salts, esters. nitriles, amides and sub stituted amides thereof. Said S-aroyl-pyrroles may be represented by the following formulas:

Ar represents a member selected from the group consisting of phenyl, thienyl, S-methylthienyl, monosubstituted phenyl and polysubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, lower alkoxy, nitro, amino, cyano and methylthio;

Ar, represents a member selected from the group consisting of phenyl, monosubstituted phenyl and polysubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl and lower alkoxy;

R represents a member selected from the group consisting of hydrogen and lower alkyl;

R represents a member selected from the group consisting of hydrogen, lower alkyl and benzyl;

R represents a member selected from the group consisting of CN, COOH, COO-(lower alkyl), CONT-I CONH--(lower alkyl), CON-(lower alkyl) CONH-OH and CONH(CH ),,-N(lower alkyl) in which n is an integer of from 2 to 4 carbon atoms;

R represents a member selected from the group consisting of COOH, COO-(lower alkyl), CONH 5 CONH-(lower alkyl) and CON-(lower alkyl) R represents lower alkyl;

R represents lower alkyl; and

R represents a member selected from the group consisting of hydrogen and lower alkyl;

10 provided that:

i. when said Ar is a member selected from the group consisting of nitro-substitutecl phenyl and aminosubstituted phenyl, then, with regard to Formula (la), said R is hydrogen, said R, is lower alkyl and said R is a member selected from the group consisting of CN, COOH and COO-( lower alkyl); and with regard to Formula (I-e), said R is hydrogen;

ii. when said Ar is cyanophenyl, then said R, is lower alkyl and said R is a member selected from the group consisting of COOH and COO-(lower alkyl); and (iii) when said R is hydrogen, then said R is hydrogen.

The non-toxic, therapeutically acceptable salts of such acids, such as are obtained from appropriate organic or inorganic bases, are also embraced within the scope of this invention.

As used herein, lower alkyl and lower alkoxy may be straight or branch chained. saturated hydrocarbons having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl,

hexyl and the like alkyls, and, respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, etc.

The subject compounds may be obtained by means of several synthetic processes. For example, the compounds of formula (l-a), in which R is CN or COO-(- lower alkyl), aregenerally prepared by a Friedel-Crafts reaction between an appropriate aroyl halide, preferably the chloride (II), and a pyrrole-2-acetic acid derivative of formula ("1), wherein R is cyano or lower alkoxycarbonyl, in the presence of a Lewis acid, preferably a metallic halide such as aluminum chloride. Suitable solvents are those typically employed in a Friedel- Crafts reaction, such as, for example, methylene chloride, 1,2-dichloroethane, carbon disulfide, nitrobenzene and the like. The acid derivative (IV) thus obtained can then be converted to the corresponding free carboxylic acid by conventional hydrolysis, for example, by heating a solution of (IV) in aqueous methanol with an alkali metal hydroxide to form the alkali metal salt of the acid and then acidifying the mixture. The foregoing reactions may be illustrated by the following schematic diagram.

0 it MC] oi it I! Ar-ii-Oi -iJrI- R rim-ii -ciiu l l R1 R1 (II) (III) IV) 0 1t NaOH 1101 All i A) A1' II-C 0 ()II N The aroyl chlorides (II) are generally known and may be obtained by transformation of the corresponding acid to the acid chloride form according to conventional procedures, such as, for example, the procedure hereinafter demonstrated in Example LXXXI.

Alternatively, to prepare the nitriles, esters and acids of formula (I-a), wherein R is lower alkyl, a 5-aroylpyrrole-2-acetic acid derivative of the formula:

wherein R is as previously desbribed, R is lower alkyl or benzyl, and Ar is thienyl, S-methylthienyl, phenyl or phenyl substituted with halo, lower alkyl, trifluoromethyl, methylthio, lower alkoxy or cyano, which acid derivative (V) may be obtained in accordance with the aforementioned Friedel-Crafts procedure, is alkylated according to conventional alkylation techniques, e.g., with a lower alkyl halide as the alkylating agent in the presence of a strong base such as sodium amide or sodium hydride, to yield the corresponding nitriles and esters:

R (VI) from which the corresponding acids are obtained by conventional hydrolysis.

The acetonitriles of formula (VI), in which R is lower alkyl, are also obtained by conventional N- alkylation of an N-unsubstituted 5-aroyl-pyrrole-2- acetonitrile of the formula:

(VII) followed by conventional C-alkylation of thethusobtained N-alkyl-5-aroyl-pyrrole-2-acetonitrile using an appropriate lower alkyl halide as the alkylating agent in each step. After the N-alkylation step or the C-alkylation step, corresponding acids may be obtained by conventional hydrolysis.

The nitriles, esters and acids of formula (I-a),

, wherein Ar is amino-substituted phenyl, are preferably In the foregoing reaction sequence, the nitro function of the S-nitrobenzoyl-l-(lower alkyl)-pyrrole-2-acetic acid ester or nitrile (obtained by the Friedel-Crafts type of reaction previously described) is catalytically hydrogenated, for example, with hydrogen and palladium-oncarbon catalyst, to yield the corresponding S-aminobenzoyl-l-(lower alkyl)-pyrrole-2-acetic acid ester or nitrile which is then hydrolyzed to the corresponding free acid form.

Esterification of the acids of formula (I-a) with a slight excess of an appropriate lower alkanol yields the corresponding esters, i.e., wherein R equals COO-(- lower alkyl). Preferably, the methyl esters of formula (I-a) are obtained by the Friedel-Crafts reaction previously described between an appropriate aroyl halide (I!) and an appropriate methyl pyrrole-2-acetate (III).

The primary amides of formula (l-a) are readily obtained by partial hydrolysis of the corresponding nitriles of formula (I-a). The nitrile-to-amide transformation is accomplished according to conventional procedures, for example, by treatment of the nitrile with aqueous sodium hydroxide under reflux for a relatively short time, that is, a period sufficient for partial hydrolysis to the amide stage as opposed to complete hydrolysis to the carboxylic acid stage. The corresponding lower alkyl-substituted amides are preferably obtained by first transforming the carboxylic function of the formula (l-a) acids into the corresponding acid chloride form, for example, by treatment of the acid or its alkali metal salt with thionyl chloride or oxalyl chloride, and then reacting the thusobtained acid chloride with an appropriate lower alkyl-amine or di(lower alkyl)-amine to yield the corresponding N-alkyl or N,N-dialkyl amides, respectively, of formula (l-a). Alternatively,, the amides of formula (l-a) may be obtained by conventional ammonolysis of the correspnding lower alkyl esters employing ammonia, or, to prepare the substituted amides of formula (I-b), by emloying an appropriately substituted amine, such as, for example, a primary lower alkylamine, a secondary lower alkylamine, an amine of the formula] H N-(CH ),,-N-(lower alkyl) in which n is the integer 2, 3 or 4, or hydroxylamine (preferably as the hydrochloride), preferably in an alcoholic solvent at elevated temperatures and in the presence of a basic catalyst normally employed in such ester to amide transformations, e. g., sodium methoxide.

The compounds of formula (I-b), wherein R is COO-(lower alkyl), preferably ethoxycarbonyl, and Ar is other than aminophenyl are prepared by a Friedel-Crafts reaction between an appropriate aroyl halide, preferably the chloride (VIII), and a lower alkyl l-(lower alkyl)-pyrrole-2-propionate (IX). Conventional hydrolysis of the thus-obtained lower alkyl 5- aroyl-l-(lower alkyl)-pyrrole-2-propionate (X) yields the corresponding free acids of formula (l-b). In turn, the esters and acids may be converted to the corresponding amides of formula (I-b) according to conventional procedures as previously described for formula (I-a) using ammonia, or an appropriate alkyl or dialkyl amine.

v Ar -Cl C C C A1013 N H:- II2 OOalkyl 1 (VIII) alkyl (IX) g one C l hydrolysis A1- 2 H2- OOaIky alkyl (X) The formula (I-b) compounds, wherein Ar is aminophenyl, are preferably obtained from the corresponding lower alkyl S-nitrobenzoyll l-(lower alkyl)-pyrrolel2propionate (obtained by the usual Friedel- Crafts type of reaction between nitrobenzoyl chloride and alkyl propionate (IX) by transforming the nitro function to an amino function according to the reaction scheme previously described for the formula (I-a) compounds, i.e., by means of catalytic hydrogenation followed by hydrolysis.

The alkyl propionates (IX) may be prepared by first treating an appropriate N-alkylpyrrole-Z- carboxaldehyde with an appropriate alkoxycarbonylmethylene triphenylphosphorane [see R. Jones et al., Canad. Jour. Chem., 18, 883 (1965)] and then hydrogenating the thus-obtained alkyl 2-(1-alkyl-2-pyrrolyl)- acrylate, thereby saturating the double bond of the acrylate function, to yield the desired alkyl propionate (IX).

The compounds of formula (I-c), wherein R is hydrogen, are prepared from an appropriate l-aryll l ,2,3- butanetrione-Z-oxime (XI) and an appropriate dialkyl acetone-dicarboxylate (XII) as starting materials. The two are contacted together according to a Knorr pyrrole synthesis in glacial acetic acid in the presence of zinc dust to yield the ring-closed pyrrole, alkyl 5-aroyl- 3-alkoxycarbonyl-4-methylpyrrole-2-acetate (XIII). Hydrolysis of the latter with moderately concentrated alkali, for example 25-50 percent aqueous sodium hydroxide gives the corresponding free di-acid (XIV) which is then partially reesterified using an acidic solution of a lower alkanol to yield the corresponding alkyl 5-aroyl-3-carboxy-4-methylpyrrole-2-acetate (XV). Decarboxylation of the carboxy group in the 3-position is then accomplished by heating the latter in a suitable basic organic solvent such as quinoline. The resulting alkyl 5-aroyl-4-methylpyrrole-2-acetate (XVI) is then hydrolyzed in the usual manner to give the desired free acids (XVII) of formula (I-c). In turn, the acids may be esterified using lower alkanols to the corresponding 5 lower alkyl esters of formula (I-c) and such acids or esters are converted to the corresponding amides of formula (I-c) according to conventional procedures using ammonia, or an appropriate alkyl or dialkyl amine. The foregoing reaction sequence may be illustrated by the following diagrammatic scheme:

COOEt CHzC O OEt HOAO (XIV) (XVI) EtOII (XVII) The compounds of formula (I-d) are prepared from the known pyrrole ester, ethyl 2,4-dimethylpyrrole- 3-acetate (XVIII), which is acylated according to a Friedel-Crafts reaction using an appropriate benzoyl halide, preferably the chloride (XIX), as the acylating agent. The methyl group in the 2-position of the thusobtained ethyl S-benzoyl-Z,4-dimethylpyrrole- 3-acetate (XX) is then perchlorinated by treating said ester (XX) with sulfuryl chloride in an inert solvent such as ether to yield the corresponding ethyl 5- benzoyl-4-methyl-2-trichloromethylpyrrole-Z-acetate (XXI). Hydrolysis of the latter, for example, by heating at reflux in aqueous dioxane or 1,2-dimeth0xyethane, for a few hours, gives the di-acid, 5-benzoyl-4-methyl- 2-carboxypyrroIe-3-acetic acid (XXII). The carboxy function on the 2-position is then removed, for example, by heating in a suitable basic organic solvent such as qunioline, to yield the desired free acids (XXIII) of formula (I-d). Again, the acids may in turn be converted to the corresponding esters, from which acids and esters the amides of formula (1-11) are produced in the usual manner. The foregoing reaction sequence may be illustrated by the following diagrammatic scheme:

The compounds of formula (l-e), wherein R is hydrogen, are prepared according to the following synthetic sequence. An appropriate chloromethyl loweralkyl ketone of formula XXIV is added to a mixture of an appropriate di-loweralkyl acetone dicarboxylate,

preferably the diethyl ester (XII), and a loweralkylamine (R Nl l preferably in an aqueous medium. The reaction temperature is preferably maintained just below 60C. and, after a few hours, the mixture is treated with ice-hydrochloric acid. The thusobtained ring-closed pyrrole, alkyl 1-loweralkyl-4- loweralkyl-3-alkoxycarbonyl-pyrrole-2-acetate (XXV) is then acylated with an appropriate aroyl halide, preferably the chloride, of the formula: Ar-COC] wherein Ar is as previously described, except for phenyl substituted with lower alkoxy, amino, cyano and methylthio, under Friedel-Crafts reaction conditions to yield the corresponding alkyl 5-aroyl-l-loweralkyl-4-loweralkyl- 3-alkoxycarbonyl-pyrrole-Z-acetate (XXVI): The foregoing reaction scheme may be illustrated as follows (the symbols R and R being as previously described):

R5 =O C O Et HH H2O III CHzC O 0 Et R4 (XXIV) (XII) 8 1T5 I ia l WCOOEIJ AICOCI WCOOEI,

Friedel- \N CHICOOElI Crafts Al-CO- N/ CHLICOOEIZ (XXV) (XXVI) The thus-obtained S-acyl product (XXVI) is then subjected to the same synthetic sequence as previously described for product (XIII), namely, the successive steps of hydrolysis, partial re-esterification, decarboxylation and hydrolysis to give the l-R -4-R -5-acyl deriv atives corresponding to products (XIV) through (XVII), respectively:

COOEt l IIOII ArC0 CH1COOEt (XXVI) 00011 EtOII Ar-CO CHQCOOH 11+ (XXVII) lin --ooon H -00) -v A1-CO N -CIIzCOOEt A (XXVIII) R5 R5 1 11011 l -D m-oo cmcoom AI'CO CII;COOI[ l l R4 R4 (XXIX) (XXX) An alternative procedure for making the compounds of formula (I-e), wherein R is hydrogen and R R and Ar are as previously described except that Ar is other than phenyl substituted with amino, comprises the hydrolysis of the di-ester (XXV), preferably under alkaline conditions, to the corresponding di-acid (XXXI) which is then partially re-esterified using an acidic solution of a lower alkanol to yield the corresponding lower alkyl l-R44R -3-carboxypyrroIe-Z-acetate (XXXII), the 3-position of which is then decarboxylated, for example, by heating in an inert atmosphere until gas evolution ceases or by heating in a suitable basic organic solvent such as quinoline, and the thusobtained lower alkyl l-R -4R -pyrrole-2-acetate (XXXIII) is then acylated with an appropriate aroyl halide, preferably the chloride, of the formula Ar-COCl under FriedeLCrafts reaction conditions to yield the corresponding ester of formula (XXXIV) which in turn may be hydrolyzed to the corresponding acid form (XXXV):

k) 600E HOH COOH EtOH -ornoo Et -ornc 0 011 l R; I l;

(XXV) XXXI R R5 LJ[coon -002 U APOOCI Friedelcrncoom cInCooEt Grafts R4 R4 (XXXII) (XXXIII) i non ArCO N -ClIzCO0Et A1'OO\N /CH1COOII l I R4 R4 (XXXV) (XXXIV) The process of making loweralkyl l,4-di-loweralkyl- 3-loweralkoxycarbonyl-pyrrole-2-acetate (XXV) and the alternative processes for making loweralkyl l-R4-4- R5-5-aroylpyrrole-2-acetates as exemplified by structures (XXIX) and (XXXIV) are deemed to be novel and, as such, these processes constitute additional features of this invention.

Alkylation of the esters (XXIX) and (XXXIV) according to standard procedures, e.g., with loweralkyl iodide as the alkylating agent in the presence of a strong base such as sodium amide or sodium hydride in a suitable organic solvent such as dimethyl sulfoxide, yields the corresponding a-loweralkyl derivatives of formula (l-e) from which the corresponding a-loweralkyl acids are obtained by conventionalhydrolysis. Such acids, together with those of formulas (XXX) and (XXXV) are readily esterified with the amides and substituted amides as defined by R in formula (I-e) are prepared by the methods previously described herein.

The compounds of formula (I-e), wherein Ar is aminosubstituted phenyl, are preferably obtained by reduction of the corresponding S-nitrobenzoyl esters of formulas (XXIX) and (XXXIV), including the a-loweralkyl derivatives thereof, according to the method previously shown for converting the 5-nitrobenzoyl derivatives of formula (I-a) to the corresponding 5- aminobenzoyl form. Similarly, the thus-obtained lower alkyl 5-aminobenzoyll -R -4-R -a-R -pyrrole- Z-acetates can by hydrolyzed to the corresponding free acid form from which the desired esters and amides defined by R of formula (I-e) may be obtained according to the usual methods previously described.

The corresponding salts of the acids of formulas (l-a, b, c, d and e) are readily obtained by treating the acids with a slight excess of an equivalent amount of appropriate base, for example, an alkali or alkaline earth metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and the like, or with an organic amine base, e.g., a lower alkylamine such as ethylamine, propylamine and the like, or other amines such as benzylamine, piperidine, pyrrolidine and the like.

The subject compounds of formulas (l-a, b, c, d and e) and the therapeutically active salts thereof have useful pharmacological properties which make them suitable for incorporation into conventional pharmaceutical forms for administration. These compounds have been found to possess anti-inflammatory activity as demonstrated in the standard kaolin-induced rat paw edema and cotton pellet granuloma tests at doses generally ranging from 5-100 mg/kg body weight.

In the kaolin-induced rat paw edema assay, the ability of a compound, when administered in a single oral dose, to inhibit the swelling of the rat paw injected with a standard amount (0.1 ml.) of 10 percent kaolin suspension in saline is measured. For comparative purposes, the activity of the compound to be tested is measured against that produced by the known antiinflammatory agent, phenylbutazone. Male Holtzman rats are used in the assay. For example, in this test, the compound 5-(p-chlorobenzoyl)-l-methyl-pyrrole-Z- acetic acid was found to exhibit an inhibition of about 35 percent at 12.5 mg/kg; about 47 percent at 25 mg/kg; and about 45-53 percent inhibition in doses of 50-100 mg/kg; whereas phenylbu'tazone exhibited an inhibition of 30-40 percent at mg/kg and 50-60 percent at mg/kg.

In the cotton pellet granuloma assay, the ability of a compound, when administered orally to male Holtzman rats daily for seven days, to inhibit the amount of granuloma tissue formed in or arounda cotton pellet implanted beneath the skin in the thoracic region of the animal is measured and compared to water controls. The method is described by Charles A. Winter and coworkers in J. Pharmacol., 141 369 (1963). Analysis of variance is used to determine the significance of the results. For example, in this test, the compound S-(panisoyl)-l -methylpyrrole-2-acetic acid exhibited a granuloma weight of about 71 mg. at a dose of 25 mg/kg as compared to 1 10 mg. with the water controls; and the compound 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile exhibited a granuloma weight of about 98 mg. at a dose of 100 mg/kg as compared to mg. with the water controls.

In the following table, the anti-inflammatory activity of several compounds of formulas (I-a, b, c, d and e) is listed, it being understood that such compounds are not listed for purposes of limiting the invention thereto, but only to exemplify the useful properties ofall the compounds within the scope of formulas (I-a, b, c, d and e), including the pharmaceutically acceptable basic salts thereof.

KAOLIN-INDUCED PAW EDEMA ASSAY DOSE (p.o.) INHIBITION mg/kg (Average rats) S-(p-chlorobenzoyl)-l-methyIpyrroIe-2-acetic acid 25 47 5-( m-chlorobenzoyl )-do 25 41 5-(o-chlorobenzoyl)-do 25 44 5-( 2 ,4-dichlorobenzoyl)-do 25 5 I 5-(p-bromobenzoyl)-do 25 42 S-(p-fluorobenzoyD-do 25 42 5-(p-methoxybenzoyl)-d0 25 42 5-(p-methylbenzoyl)-do 25 44 5-( p-nitrobenzoyl )-do 100 35 5-(p-aminobenzoyl)-do 25 23 5-(p-cyanobenzoyI)-do I00 S-benzoyl-do 25 38 5-(p-chlorobenzoyl)-a-methyl-l-methylpyrrole-2-acgticagid 50 56 5-(p-chlorobenzoyl)-a-ethyl-l-methylpyrrole-Z-acetic acid 25 2 2 5-(p-chlorobenzoyl)-pyrrole-2-acetic acid 25 I 32 S-(p-chlorobenzoyl)-l-ethyl yrroIe-Z-acetic acid 100 43 Y l-benzyl-5-(p-chlorobenzoy )-pyrrole-2-acetic acid '50 23 ethyl 5-(p-chlorobenzoyl)-l-methylpyrrole-Z- acetate 25 37 methyl 5-(p-ehlorobenzoyl)-l-methylpyrrole-Z- acetate 25 33 5-(p-chlorobenzoyl)-l-methyIpyrrole-2-acetamide 5O 35 5-( p-chlorobenzoyl )-N-ethyl- I -methylpyrroIe-2- acetamide 25 25 5-( p-chlorobenzoyl )-N,N-diethyll-methylpyrrole-Eetgmide 25 36 S-(p-chlorobenzoyl) l-methylpyrrole-Z-propionic acid 25 63 5-( p-chlorobenzoyl )-4-methylpyrrole-3-acetic acid 43 5-benzoyl-4-methylpyrrole-2-acetic acid I00 34 (+)-5-(p-chlorobenzoyl)-a-methyll-methylpyrrole-Z-acetic acid 25 62 ()-5-(p-chlorobenzoyl)-a-methyll-methylpyrrole-Z-acetic acid 25 24 5-(5-methylthenoyl)-l-methylpyrrole-Z-acetic acid 25 48 5-(2-thenoyI)-do 25 63 5-(p-trifluoromethylbenzoyl)-do 25 60 5-(o-methylbenzoyI)-do l2.5 34 S-(p-chlorobenzoyh-l-methyl pyrrolc-2-acetohydroxamic ac 25 33 S-(p-chlorohenzoyl)-N-( 2-dicthylaminocthyl)-l-mcthylpyrrole- 2-ucctamlde 25 27 Due to their surprisingly marked potency and/or low toxicity profile, the compoundsof formula (I-e) are among the preferred compounds described herein, particularly when R is loweralkyl (preferably methyl). For example, in the kaolin-induced rat paw edema assay, a 51 percent inhibition was observed with 5-(pchIorobenzoyl)-l,4-dimethylpyrrole-2-acetic acid at a dose of 2.5 mg/kg; 29 percent inhibition at 3.0 mg/kg and 47 percent inhibition at 9.0 mg/kg with 5-(pchlorobenzoyl)-4-ethyl-l-methylpyrrole-Z-acetic acid, and 37 percent inhibition at 3.0 mg/kg and 53 percent inhibition at 9.0 mg/kg with 5-(p-chlorobenzoyl)-amethyl-l,4-dimethyI-2-acetic acid. Other preferred compounds are those embraced within formulas (I-a, b, c, d and e) wherein the Ar or Ar function is halo phenyl, most preferably chlorophenyl, and the R or R function is COOI-I or COO(lower alkyl).

As anti-inflammatory agents, the compounds of formulas (I-a, b, c, d and e) and salts thereof are of value in reducing inflammation and alleviating the symptons of rheumatic, arthritic and other inflammatory conditions. The compounds can be administered in therapeutic dosages in conventional pharmaceutical formulations for oral and parenteral administration, for example, tablets, capsules, solutions, suspensions, elixirs, injectables and the like.

As is evident from the previously described methods of forming the subject compounds, many of the compounds of formulas (I-a, b, c, d and e) are also useful as intermediates in the syntheses of other compounds thereunder. For example, the nitriles and esters represented by formulas (IV, V, VI and VII) are useful intermediates in the syntheses of corresponding acids. In addition, the S-nitrobenzoyl compounds of formulas (l-a) and (I-b) are useful intermediates in the transformation procedure to corresponding S-aminobenzoyl compounds. Moreover, the acids embraced within formulas (I-a, b, c, d and e) are useful intermediates in the transformation procedures to corresponding esters, amides and basic salts.

Due to the available asymmetric a-carbons present in the subject compounds of formulas (I-a) and (I-e), it is evident that their existence in the form of stereochemical isomers (enantiomorphs) is possible. If desired, the

resolution and isolation or the production of a particular form can be accomplished by application of general principles known in the art. Said enantiomorphs are naturally intended to be included within the scope of this invention.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAMPLE I sulfide solvent is then decanted and discarded. The The red gummy residue is washed with hexane and dilute hydrochloric acid and ice is added to the mixture. The mixture is extracted with ether. The ether solution is shaken with an aqueous solution of dimethylaminopropylamine and washed with dilute hydrochloric acid followed by brine. The solution is dried over magneshim sulfate and treated with charcoal. After removal of the charcoal, the solvent is evaporated in vacuo leaving a partially crystalline red oil as a residue. This material is extracted with three 500 ml. portions of boiling pentane. The combined pentane extracts are evaporated in vacuo and the residue is crystallized from 60 ml. of cold methanol. The resulting solid is collectedand washed with cold methanol; there is obtained about 6.3 g. of white crystalline solid, ethyl -(pchlorobenzoyl)-l-methylpyrrole-2-acetate, m.p. 7476C. Recrystallization from methyl cyclohexane raises the melting point to 7880C.

EXAMPLE ll 5-(p-Chlorobenzoyl)-l-methylpyrrole-Z-acetic acid and its sodium salt: A suspension of 3.06 g. (0.01 mole) of ethyl-5-( p-chlorobenzoyl)- l -methylpyrrole- 2-acetate in 25 ml. of 0.5 N sodium hydroxide is refluxed for 30 minutes. About two-thirds of this solution is cooled, washed with ether, and then acidified with dilute hydrochloric acid. The resulting solid precipitate is collected by filtration, dried and recrystallized from ethanol-water to give the product, 5-(pchlorobenzoyl)-l-methylpyrrole-2-acetic acid; m.p. l89-l9lC. Upon recrystallization from ethanolwater, the melting point is l88190C. The other onethird of the solution is cooled in an ice-bath whereupon the yellow sodium salt of the acid is precipitated and collected by filtration.

chloride is employed in place of the pchlorobenzoylchloride used in Example I, there are obtained as respective products, ethyl S-benzoyl-lmethyl-pyrrole-2-acetate and S-benzoyl-l-methyl-pyrro1e-2-acetic acid.

EXAMPLE IV 5-Benzoyl-l-methylpyrrole-2-acetonitrile: To a chilled suspension of 9.7 g. (0.07 mole) of aluminum chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solution of 1-methy1pyrrole-2- acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5C.). After the addition is complete, the reaction mixture is stirred at 0C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with N,N- dimethyl-1,3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240260 mg. range contain the desired product. These fractions are combined, the solvent evaporated off and the oily residue, when triturated with methanol, yields the crystalline product, S-benzoyl-l-methylpyrrole-2acetonitrile, m.p. 106-108C.

EXAMPLE V S-Benzoyl-l-methylpyrrole-2-acetic acid: A suspension of 2.42 g. (0.11 mole) of 5-benzoyl-l-methylpyrrole-2-acetonitrile, 0.9 g. (0.22 mole) sodium hydroxide, 6 ml. water, and 0.5 ml. ethanol, is stirred and refluxed for one hour. The resulting solution is cooled and extracted in water and chloroform. The aqueous fraction is made acidic with 3N hydrochloric acid. A white solid, S-benzoyl-l-methylpyrrole-2-acetic acid, precipitates which is filtered and washed with a hexaneether solution, m.p. l44-l45C.

Found: c,s ZHI Analysis: Calcd. for C H CINO C, 60.54; H, 4.3 Found: C, 60.54; H, 4.3

EXAMPLE III EXAMPLE v 5-(m-Chlorobenzoyl)- l -methylpyrrole-2- acetonitrile: To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in ml. 1,2-dichloroethane is added dropwise 23 g. (0.12 mole) mchlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of IS g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-

dichloroethane. The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified,

with 3N hydrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3- propanediamine, 3N-hydrochloric acid and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is triturated with cold methanol to yield a precipitate of the desired:

product which is filtered off and set aside. The methanol filtrate is concentrated in vacuo and the remaining oily residue is chromatographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. About 2.5 g. of the desired product are isolated by evaporation of the first few compound-bearing (ether) fractions. The solids are combined and recrystallized from methanol to yield about 3.6 g. of 5-(mchlorobenzoyl) -l-methylpyrrole- 2-acetonitri1e, m.p. -122127C.

Analysis: Calcd. for C H CIN- O: N, 10.83% Found: N, 10.52%

EXAM PLE Vll 5-(m-Chlorobenzoyl)-1-methylpyrrole-2-acetic acid: A mixture of 2.8 g. (0.01 mole) of 5-(mchlorobenzoyl)-1-methy1pyrrole-2-acetonitri1e, 22 ml. of 1N sodium hydroxide solution and 5 ml. ethanol is stirred at reflux for hours. Some of the ethanol is evaporated. The remaining solution is poured into ice acidified with dilute hydrochloric acid. A white solid, 5-(m-ch1orobenzoy1)-1-methy1pyrro1e-2-acetic acid, precipitates which is recrystallized twice from methanol: water, m.p. 165C.

l6 5-( p-bromoben zoyl l -methylpyrrole-2-acetic acid, m.p. 188C; and 5-(p-fluorobenzoy1)- 1 -methy1pyrrole-2-acetic acid,

m.p. 164-l 65C.

EXAMPLE IX 5 o ChlorobenzoyD- l -methylpyrrole-2-acetonitri1e: To a cooled suspension of 14 g. (0.105 mole) aluminum chloride in 45 ml. dichloroethane is added dropwise, 18.5 g. (0.105 mole) o-chlorobenzoyl chloride.

The resulting solution is added dropwise to a cooled (0C.) solution of l-methylpyrrole-2-acetonitrile in 45 m1. dichloroethane keeping the temperature at approximately 10C. The mixture is stirred at room temperature for about twenty minutes, and then refluxed for three minutes. It is poured into ice acidified with 3N hydrochloric acid and the resulting two layers are separated. The aqueous fraction is extracted twice with EXAMPLE X 5-(o-Ch1orobenzoyl)-l-methylpyrrole-Z-acetic acid: A solution of 2.4 g. (0.009 mole) of 5-(0- chlorobenzoyl)-1-methylpyrrole-2-acetonitri1e, 18 ml.

Analysis: Calcd. for C H CINO C, 6

0.5 N. .0 Found: C, 60.6 N 8 4', H, 4.36; 5 5 l; H, 4.40; 4. 7

EXAMPLE Vlll A. The procedure of Example V1 is repeated except that an equivalent quantity of p-bromobenzoyl chloride and p-fluorobenzoyl chloride is used in place of the mchlorobenzoyl chloride used therein to yield, as respective products: 5-(p-bromobenzoy1)-1-methylpyrro1e-2-acetonitrile, m.p. 139-141C; an

of 1N sodium hydroxide and 18 ml. percent ethanol is stirred and refluxed for seven hours. The ethanol is evaporated off and the remaining solid residue is dissolved in water and washed with chloroform. The aqueous layer is made acidic with 3N hydrochloric acid. An oil precipitates which crystallizes when scratched. The solid is filtered and washed with water and hexane. The solid is. purified by recrystallization from methanolzwater and again from ether:hexane, m.p. -141C.

Analysis: Calcd. for C H CINO C, 60.

Found: C, 6

5-(p-fluorobenzoy1)-1-methylpyrrole-2-acetonitri1e, m.p. 134-136C.

B. By following the procedure of Example Vll, using an equivalent quantity of the foregoing acetonitriles in place of the 5-(m-chlorobenzoyl)-1-methylpyrrole-2- acetonitrile used therein, the following respective acids are obtained:

EXAMPLE XI 5-(2 ',4 '-Dich1orobenzoy1)- 1 -methy1pyrro1e-2- 65 acetonitrile: To a suspension of 16.6 g. (0.125 mole) of aluminum chloride in 60 m1. 1,2-dichloroethane is added 26.2 g. (0.125 mole) of 2,4-dichlorobenzoyl chloride. The resulting solution is added slowly to a solution of g. (0.125 mole) of l-methylpyrrole-2- acetonitrile in 60 ml. l,2-dichloroethane while cooling externally with an ice bath. After the addition is complete, the mixture is stirred for forty minutes at room temperature followed by heating at reflux for three minutes. It is then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyll ,3- propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting red oily residue is chromatographed on a column packed with neutral alumina and eluted with benzene and ether. The first compound-bearing fractions upon evaporation yield a white solid, 5-(2,4'- dichlorobenzoyl)- l -methylpyrrole-2-acetonitrile, which is purified by recrystallization from methanol, m.p. l29l30C.

Analysis: Calcd. for C H Cl N O: N, 9.56% Found: N, 9.51%

EXAMPLE XII using hexane, benzene and ether as successive solvents. The product is isolated by concentrating in vacuo the first few major compound-bearing fractions 10 percent ether in benzene). The solids are combined and recrystallized from methanol and? then from benzenehexane, m.p. lO2-l05C.

EXAMPLE XIV 5-(p-Toluoyl)-l-methylpyrrole-Z-acetic acid: A solution of 3.67 g. (0.015 mole) of 5-(p-toluoyl)-lmethylpyrroIe-Z-acetonitrile, 24 ml. of 1N sodium hydroxide, and 50 ml. of 95 percent ethanol is stirred and refluxed for twenty-four hours. The resulting solution is poured into ice acidified with dilute hydrochloric acid. A white solid precipitates which is extracted into ether. The ether phase is washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated and a white solid, 5-(p-toluoyl)-l-methylpyrrole 2-acetic acid, is obtained which is recrystallized twice from isopropanol, m.p. l55-l57C.

EXAMPLE XV A. By repeating the procedure of Example XI, except that an equivalent quantity of o-toluoyl chloride, mtoluoyl chloride, p-ethylbenzoyl chloride and 3,4- dimethylbenzoyl chloride is used in lieu of the 2,4- dichlorobenzoyl chloride used therein, there are obtained as respective products the corresponding 5-(0- toluoyl),5-(m-toluoyl), S-(p-ethyllbenzoyl and 5-(3', 4-dimethylbenzoyl) derivatives of l-methylpyrrole-Z- acetonitrile.

B. The procedure of Example XII is repeated, using an equivalent quantity of each of the foregoing acetonitriles in place of the 5-(2', 4'-dichlorobenzoyl)-l- EXAMPLE XIII 5-(p-Toluoyl)-l-methylpyrrole-2-acetonitrile: To a cooled suspension of 26.6 g. (0.2 mole) aluminum chloride in 80 ml. dichloroethane is added dropwise 30.8 g. (0.2 mole) p-toluoyl chloride. The resulting solution is added dropwise to a solution of l-methylpyrrole-2-acetonitrile in 80 ml. dichloroethane cooled externally with an ice bath. After the addition, the resulting solution is stirred at room temperature for twenty minutes and then refluxed for three minutes. The solution is poured into ice acidified with dilute hydrochloric acid. The organic and aqueous fractions are separated. The aqueous fraction is extracted once with chloroform. The organic fractions are combined and washed successively with N,N-dimethyll ,3- propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated off. Upon trituration of the residue with methanol, a solid crystallizes, 5-(p-toluoyl)-l-methylpyrrole- 2-acetonitrile, which is removed by filtration and purifled by recrystallization from benzene. Additional product is isolated from the mother liquors which are combined, concentrated in vacuo and the resulting oily residue column chromatographed on neutral alumina methylpyrrole-Z-acetonitrile used therein, to yield as respective products the corresponding 5-(o-toluoyl), 5-(m-toluoyl), S-(p-ethylbenzoyl) and 5-(3', 4'- dimethylbenzoyl) derivatives of l-methylpyrrole-2- acetic acid.

EXAMPLE XVI dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give a dark oily residue which is crystallized from 40 ml. of cold methanol. The solid is collected by filtration, washed with cold methanol and recrystallized from methanol to give white crystalline methyl 5-(p-anisoyl)-l-methylpyrrole-Z-acetate, m.p. l04-l05C.

3,865,840 19 20 EXAMPLE XVII The resulting white precipitate, -(3-chloro-ptoluoyl)-l-methylpyrrole-2-acetic acid, is filtered off and purified by recrystallization once from isopropan01, m.p. 176-l78C.

5-(p-Anisoyl)-l-methylpyrrole-Z-acetic acid: A solution of 3.00 g. (0.0.105 mole) of methyl 5-(p-anisoy1)- l-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of 1N sodium hydroxide solution and 5 ml. of 95 percent 5 ethanol is refluxed for 30 minutes. The solution is di- EXAMPLE XXI luted with water and the ethanol is evaporated in By repeating the Friedel-Crafts procedures of Examvacuo. The solution is filtered and the filtrate acidified ple XVI with an equivalent amount of an appropriately with dilute hydrochloric acid. The precipitated solid is substituted benzoyl chloride, the following 5-aroyl decollected by filtration, dried and recrystallized from rivatives of methyl l-methylpyrrole-2-acetate are obmethanol-water to give about 2.4 g. (87 percent yield) tained:

of white 5-(p-anisoyl)-l-methylpyrrole-Z-acetic acid, methyl 5-(3,4-dimethoxybenzoyl)-l-methylpyrrolem.p. 170l7lC. Z-acetate;

Analysis: Calcd. for C,5H',5NO,,: C, 65.92; H, 5.53; N, 5.13% Found: C, 66.01; H, 5.62, N, 5.12%

EXAMPLE XVIII methyl 5-(3',5'-dinitrobenzoyl)-l-methylpyrrole- Z-acetate;

methyl 5-(3-bromo-4'-chlorobenzoyl)-l-methylpyrrole-2-acetate;

methyl 5-(2,3,5'-tribromobenzoyl)-l-methylpyrrole-2-acetate; and

methyl 5-(3,4',5-trimethoxybenzoyl)-l-methylpyrrole-2-acetate.

By repeating the procedures of Examples XVI and XVII successively, except that an equivalent quantity each of m-anisoyl chloride and p-ethoxybenzoyl chloride is initially employed in place of p-anisoyl chloride, there are obtained as ester products, the corresponding 5-(m-anisoyl) and S-(p-ethoxybenzoyl) derivatives of methyl 1-methylpyrrole-Z-acetate, and as acid products, the corresponding S-(m-anisoyl) and 5-(pethoxybenzoyl) derivatives of 1-methylpyrrole-2-acetic EXAMPLE acid, respectively. The transformation of an acetic acid ester function to an acetic acid function according to the hydrolysis pro- EXAMPLE XIX cedure of Example XVII is repeated with an equivalent 5 3' 1 1 -1 1 2 amount of each of the pyrrole-acetates obtained in Exacetonitrile: 21.4 Grams (0.114 mole) of 3-chloro-4- ample XXI to yield, as respective Products the Corremethylbenzoylchloride is added to a suspension of 15.2 sponding y y py acidsg. (0.114 mole) aluminum chloride in 50 m1. l,2-

dichloroethane. The resulting solution is added drop- EXAMPLE wise to a chilled solution of 13.7 g. (0.114 mole) of l- -(P- r yU-I-m hylpyrr0l -2-acetonitri1e: methylpyrrole-2-acetonitrile in 50 ml. 1,2- 40 A solution of 46.4 g. (0.25 mole) of p-nitrobenzoyl dichloroethane. After the addition is complete, the Ch o de in 100 ml. l,2-dichl0r0ethane is added pormixture is stirred for ten minutes at room temperature tionwise to a suspension of 32.2 g. (0.25 mole) aillmiand then heated to reflux for three minutes. It is poured num chloride in 100 ml. l,2-dichloroethane. This mixinto ice acidified with dilute I-ICl. The organic phase is ture is added dropwise to a chilled solution of 30.0 g. separated and washed consecutively with N,N-dimethmole) hylpyrr 1e-2-a tonitrile in 100 ml.

yl-l ,3-propanediamine, 3N hydrochloric acid and satul,2-dichloroethane. After the addition is complete, the rated sodium chloride solution. It is then dried over ani ture iS Stirred for twenty minutes at room temperahydrous magnesium sulfate and the solvent evaporated lure and refluxed four minutes It is Poured ff A white solid, 5 3' 1 1 into ice acidified with 3N hydrochloric acid. The 0rroIe-Z-acetonitrile, precipitates from the resulting oily game Phase is Separated and Washed successively with residue upon trituration with methanol which is purii y i -p p 3N hydrochloric fied by recrystallization from methanol, m.p. acid and saturated sodium chloride solution. It is then ll6-l 18C. dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting semi-solid residue is triturated with cold methanol from which the product, 5-(pnitrobenzoy1)-1-methylpyrrole-2-acetonitrile, crystal- Analysls: Calcd' gmi i 333; lizes. It is removed by filtration and purified by recrystallization from acetone, m.p. l67-169C.

EXAMPLE XXIV EXAMPLE Xx 5-(p-Aminobenzoyl)-l-methylpyrrole-2-acetonitrile: -py -m thylpyrr l -2-a A solution of 7 g. (0.026 mole) of 5-(p-nitrobenzoyl)- acid: A Solut on o gmole) of 1-methylpyrrole-2-acetonitrile in 450 ml. of ethyl acech1oro-p-toluoyl)-1methylpyrrole-Z-acetonitrile in 18 tate containing 1 g. palladium-on-carbon catalyst is hyml. percent ethanol and 26 ml. lN sodium hydroxdrogenated in a Parr shaker under 44 p.s.i. of hydrogen ide is heated at reflux overnight. The reaction mixture until the theoretical amount of hydrogen is consumed. is' then cooled and poured into dilute hydrochloric acid. The catalyst is filtered off and the solvent evaporated in vacuo. About 6.0 g. (97 percent yield) of a yellow solid, 5 -(p-aminobenzoyl 1 -methylpyrrole-2- acetonitrile remains, m.p. 137-142C.

EXAMPLE xxv 5-(p-Aminobenzoyl)- l -methylpyrrole-2-acetic acid: A suspension of 6.0 g. (0.025 mole) of 5-(paminobenzoyl)-l-methylpyrrole-2-acetonitrile, 25 ml. 95 percent ethanol and 25 ml. 1N sodium hydroxide is refluxed overnight. The ethanol is then evaporated in vacuo and the remaining suspension is poured into ice acidified with dilute hydrochloric acid to pH 5. The resulting solid is partitioned between sodium bicarbonate solution and chloroform. The insoluble substances are filtered from the two-phase mixture. The sodium bicarbonate layer is separated and acidified slowly with dilute hydrochloric acid. Solids precipitate at various pI-Is which are separated by'filtration. The desired product, 5-(p-aminobenzoyl)-l-methylpyrrole-2-acetic acid, precipitates at pH 3, m.p. l73-l75C.

EXAMPLE XXVI Ethyl 5-(p-Nitrobenzoyl)-l-methylpyrrole-2-acetate: A solution of5.5 g. (0.03 mole) of p-nitrobenzoyl chloride in 60 ml. methylene chloride is added to a suspension of 3.9 g. (0.03 mole) aluminum chloride in 20 ml. methylene chloride. The resulting suspension is added dropwise to a chilled (15C.) solution of ethyl l-methylpyrrole-2-acetate in 50 ml. methylene chloride. The solution is stirred for 15 minutes at lC. and at room temperature for 15 minutes. The reaction mixture is poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-l ,3-propanediamine, 3N hydrochloric acid and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo. A solid, ethyl 5-(pnitrobenzoyl)-l-methylpyrrole-2-acetate, crystallizes from the remaining oily residue which is isolated by recrystallization from methanol, m.p. l03-l06C.

EXAMPLE XXVII 5-(p-Nitrobenzoyl)-l-methylpyrrole-2-acetic acid: A solution of 3.2 g. (0.01 mole) of ethyl 5-(pnitrobenzoyl)-l-methylpyrrole-2-acetate and 25 ml. ethanol is brought to reflux. To this is added dropwise inl. of 1N sodium hydroxide solution. After the addition is complete, the ethanol is evaporated and the residue is acidified with dilute hydrochloric acid. The resulting solid, 5-(p-nitrobenzoyl)-l-methylpyrrole-2- acetic acid, is separated by filtration and purified by recrystallization from ethanol, m.p. l92-195C.

EXAMPLE XXVIII Ethyl S-(p-cyanobenzoyl l -methylpyrrole- Z-acetate: A solution of 5.0 g. (0.03 mole) of pcyanobenzoyl chloride in 60 ml. of methylene chloride is added to a suspension of 40 g. of aluminum chloride in 30 ml. methylene chloride. The resulting mixture is added dropwise to a chilled solution of 5.0 g. (0.03 mole) of ethyl l-methylpyrrole-2-acetate in ml. of methylene chloride. The resulting mixture is stirred at room temperature for minutes, and then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated, washed successively with N,N-

dimethylaminopropylamine, 3N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo. The resulting solid, which separates from the oily residue on standing, is recrystallized from methanol to give pure ethyl 5-(pcyanobenzoyD-l-methylpyrrole-2-acetate, m.p. 1 l7-l20C.

EXAMPLE XXIX EXAMPLE XXX Methyl 5-(p-methylthiobenzoyl)-l-methylpyrrole- 2-acetate is obtained by repeating the procedure of Example XVI except that an equivalent quantity of p-methylthiobenzoyl chloride is used in place of the panisoyl chloride used therein.

EXAMPLE XXXI 5-(p-Methylthiobenzoyl)-l -methylpyrrole-2-acetic acid is obtained by repeating the hydrolysis procedure of Example XVII except that the hydrolysis is performed on an equivalent amount of the ester obtained from Example XXX.

EXAMPLE XXXII Ethyl 5-( p-chlorobenzoyl)-a-methyll -methylpyrrole-2-acetate: A solution of 6.68 g. (0.0219 mole) of ethyl 5-(p-chlorobenzoy1)-1-methylpyrrole-2-acetate in 50 ml. of ether is added to a solution of 0.94 g. (0.024 mole) of sodamide in about ml. of liquid ammonia at 33C. The mixture is allowed to reflux for 15 minutes and 3.10 g. (0.0219 mole) of methyl iodide is added. The mixture is stirred for one hour; then the ammonia is allowed to boil off. Ether and enough ammonium chloride to neutralize any anion are added. The mixture is poured into dilute hydrochloric acid and the ether solution is separated and washed with sodium bisulfite solution, sodium bicarbonate solution and brine. It is dried over anhydrous magnesium sulfate and evaporated to give about 6.8 g. of an oily residue which crystallizes upon standing. The solid is recrystallized successively from cyclohexane and methanol to give a white crystalline solid, ethyl 5(p-chlorobenzoyl)-amethyl-1-methylpyrrole-2-acetate, m.p. 6768C.

EXAMPLE XXXII] A. 5-( p-Chlorobenzoyl )-a-methyll -methylpyrrole- Z-acetic acid: A solution of 4.05 g. (0.0126 mole) of ethyl 5-(p-chlorobenzoyU-a-methyl-l-methylpyrrole' Z-acetate, 15 ml. of 1N sodium hydroxide solution and 2 ml. of ethanol is refluxed for 30 minutes. The solution is cooled, diluted with water and filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitated solid is collected and recrystallized from methanol-water to give a white crystalline solid, S-(pmethanol chlorobenzoyl )-a-methyll -methylpyrrole-2-acetic acid, m.p. 135-1 36C.

Analysis: Calcd. for C H ClNO C, 61.7 Found: C, 61.6

B. The a-methyl acid of Example XXXllI-A is heated under reflux for a few hours withan excess of anhydrous methanol in the presence of a trace of dry hydrogen chloride to yield the corresponding methyl ester.

EXAMPLE XXXIV 5-( p-Chlorobenzoyl)-a-methyll -methylpyrrole-2- acetonitrile: To a suspension of sodium hydride (12.2 g. of 50 percent w/w NaH in mineral oil) in 1,2- dimethoxyethane is added 5-(p-chlorobenzoyl)-lmethylpyrrole-2-acetonitrile (62.6 g., 0.24 mole) in l,2-dimethoxyethane over a period of 6 hr. at room temperature. After the addition is complete, the mixture is stirred for 1 hour and then 35 g. (0.25 mole) of methyl iodide is added. The reaction mixture is stirred for an additional 3 hrs., concentrated under reduced pressure, diluted with water and extracted with chloroform. After drying, the chloroform is removed leaving a brown solid residue which is triturated with cold to give yellow crystals of 5-(pchlorobenzoyl)-a-methyll -methylpyrole-2- acetonitrile, m.p. l45-l48C. Two recrystallizations from methanol raises the m.p. to l.5l52.5C.

mixture is allowed to warm to room temperature and the ammonia allowed to escape. Ether is added and the mixture poured into dilute hydrochloric acid. The ether layer is separated and the aqueous layer is washed with ether. The combined ether solutions are washed successively with sodium bisulfite solution and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give about 7.4 g. ofa yellow oily residue containing ethyl 5-(p-chlorobenzoyl)- a-ethyl-l-methylpyrrole-2-acetate, which is used as such in the following transformation to acid procedure.

A 6.9 g. sample of the oily residue is dissolved in 30 ml. of ethanol and l 1.4 ml. of 1N sodium hydroxide is added. The mixture is refluxed for 1 hr. The solvent is then evaporated in vacuo and the residue partitioned between ether and water. The aqueous layer is separated and acidified with dilute hydrochloric acid. The precipitated oil, which is separated, crystallizes on scratching to give a solid, S-(p-chlorobenzoyU-ozethyl-l-methylpyrrole-Z-acetic acid, which is collected and dried, m.p. 108-1 12C. After successive recrystallizations from ether-methylcyclohexane, benzenehexane, methylcyclohexane and ether-hexane, the m.p. is 1l0114C.

Analysis: Calcd. for C H ClNO C, 62.84;

H, Found: C, 63.0l; H,

EXAMPLE XXXV concentrated. The residual solid is combined with theprevious solid and recrystallized from methanol-water to give the pure product, 5-(p-chlorobenzoyl)-amethyl-l-methylpyrrole-2-acetic acid, m.p. l39-141C.

EXAMPLE XXXVI 5-(p-Chlorobenzoyl)-a-ethyl-l-methylpyrrole-2- acetic acid: A solution of 6.5 g. (0.021 mole) of ethyl 5-(p-chlorobenzoyl)-l-methylpyrrole-2-acetate in 60 ml. of ether is added to a suspension of 1.25 g. (0.032 mole) of sodamide in 150 ml. of refluxing liquid ammonia. After 10 minutes, 4.98 g. (0.032 mole) of ethyl iodide is added The mixture is stirred for 1.5 hrs. and an additional 1.0 g. (.0064 mole) of ethyl iodide is added.

EXAMPLE XXXVI] The alkylation and ester-to-acid transformation procedures of Example XXXVI are repeated except that an equivalent amount of an appropriate S-aroyl-lmethylpyrrole-Z-acetic acid alkyl ester and an equivalent amount of appropriate alkyl halide alkylating agent are employed to yield the following products:

S-benzoyl-a-(n-butyU-1'methylpyrrole-2-acetic acid;

S-(p-methoxybenzoyl )-a-methyll -methylpyrrole-2- acetic acid; S-benzoyl-a-(n-propyD- l -methylpyrrole-2-acetic acid; and 5-(p-cyanobenzoyl)-a-methyl-l-niethylpyrrole-2- acetic acid.

EXAMPLE XXXVIII The alkylation and nitrile-to-acid transformation procedures of Examples XXXIV and XXXV, respectively, are repeated except that an equivalent amount of an appropriate 5-aroyl---methylpyrrole-2-acetonitrile and an equivalent amount of an appropriate alkyl halide alkylating agent are employed to yield the following products:

5-(m-chlorobenzoyl)-a-methy|- l -mcthylpyrrolc-2- acetic acid; S-(p-fluorobenzoyl )-a-ethyl- 1 -methylpyrrole-2- acetic acid;

25 -(p-methylbenzoyl)-a-ethyl-1-methylpyrrole-2- acetic acid; 5-(2',4 '-dichlorobenzoyl)-oz-methyl-1-methylpyrrole-2-acetic acid; and 5-(3'-chloro-4'-methylbenzoyl)-a-ethyl-lmethylpyrrole-Z-acetic acid EXAMPLE XXXIX 5-(p-Chlorobenzoyl)-pyrrole-2-acetonitrile: To a chilled suspension of 26.80 g. (0.2 mole) of aluminum chloride in 110 ml. of methylene chloride is added dropwise 35 g. (0.2 mole) of p-chlorobenzoyl chloride. The mixture is added dropwise to a solution of 21.22

g. (0.2 mole) of pyrrole-Z-acetonitrile in 125 ml. methylene chloride which is cooled externally with an ammonium chloride ice bath. After addition is complete, the reaction mixture is stirred for ten minutes at 0C. and then poured into ice acidified with dilute hydrochloric acid. A solid precipitates, 5-(p -chlorobenzoyl)- pyrrole-2-acetonitrile, which is filtered off, washed with hot methanol and dried, m.p. 203205C.

EXAMPLE XL 5-(p-Chlorobenzoyl)-pyrrole-2-acetic acid: A solution of 3.6 g. (0.015 mole) of 5-(p-chlorobenzoyl)- pyrrole-2-acetonitrile, ml. 1N sodium hydroxide solution, and 30 ml. 95 percent ethanol is refluxed and stirred for 6 hours. The ethanol is evaporated off in vacuo. The resulting solid is dissolved in water and the 30 solution filtered from insolubles. The filtrate is acidified with dilute hydrochloric acid. A white solid precipitates, 5-(p-chlorobenzoyl)-pyrrole-2-acetic acid, which is purified by recrystallization from acetoneswater (121), mp. 210C.

EXAMPLE XLI 26 5-( 3 '-chloro-4 -methylbenzoyl )-pyrrole-2-acetic acid; and 5-(2',4-dichlorobenzoyl)-pyrrole-2-acetic acid.

EXAMPLE XlLlll 5-(p-Chlorobenzoyl)-l-ethylpyrrole-2acetonitrile:

A mixture of 24.4 g. (0.1 mole) 5-(p-chlorobenzoyl)- pyrrole-Z-acetonitrile, 41.7 g. (0.3 mole) of potassium carbonate and 16.1 g. (0.105 mole) of ethyl iodide in 300 ml. of methylethylketone is refluxed overnight. The reaction mixture is then poured into water and extracted with chloroform. The organic solutions are combined, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue is crystallized from 2-propanol to give about 13 g. of crude solid. The solid is sublimed overnight at 140C. and 0.025 mm.. Hg. The sublimate is successively recrystallized from 2-propanol, benzene and hexane to give 5-(p-chlorobenzoyl)-l-ethylpyrrole-2-acetonitrile as a white solid, mp. l-l47C.

Analysis: Calcd. for C H CIN O: N, 10.27% Found: N, 10.54%

EXAMPLE XLllV 5-(p-Chlorobenzoyl)-l-ethylpyrrole-Z-acetic acid: A suspension of 3.52 g. (0.013 mole) of 5-(pchlorobenzoyl)-l-ethylpyrroIe-Z-acetonitrile in 26 ml. 1N sodium hydroxide and ml. of ethanol is refluxed for six hours. The mixture is then diluted with water and cooled. A solid precipitates which is filtered off and set aside. The ethanol is evaporated from the filtrate in vacuo. The collected precipitate is added to the concentrated filtrate and the mixture is extracted with chloroform. The aqueous phase is separated, acidified with dilute hydrochloric acid, and the resulting precipi- 0 tate (A) is collected by filtration and dried. The chloroform phase is evaporated and the residue refluxed with 12 ml. of 1N sodium hydroxide and 24 ml. of ethanol for 6 hours. The ethanol is evaporated in vacuo and the remaining solution is diluted with water and washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and the precipitated solid (B) is collected and dried. The two samples of acidic material (A and B) are combined and recrystallized from aqueous isopropanol to give 5-(p-chlorobenzoyl)-lethylpyrrole-Z-acetic acid as a white solid, mp. l49l53C.

Analysis: Calcd. for C H ClNO C, 6

1.75; H, 4.83; N, 4.80% Found: C, 61.78; H, 4.94; N, 4.96%

EXAMPLE XL" EXAMPLE XLV The N-alkylation procedure of Example XLIlI is followed to prepare 5-aroyl-1-R -pyrrole-2-acetonitriles wherein R, is lower alkyl. For example, by repeating such procedure with an equivalent amount of an appro priate N-unsubstituted 5-aroyl-pyrrole-2-acetonitrile and an equivalent amount of an appropriate alkyl halide as the N-alkylating agent, the following respective products are obtained:

successively with N,N-dimethylaminopropylamine so- -benzoyll -ethylpyrrole-2acetonitrile; S-(p-methylbenzoyl l -(n-propyl)pyrrole-2- acetonitrile; 5-(p-m ethoxybenzoyl l -ethylpyrrole-2-acetonitrile;

and I 5 5-( 2,4 -dichlorobenzoyl)- l -(n-butyl)pyrrole-2- acetonitrile.

, EXAMPLE XLVl The nitrile-toacid transformation procedure of Example XLIV is repeated, except that an equivalent amount of each acetonitrile obtained in Example XLV is used as the starting acetonitrile to yield the following respective products:

S-benzoyl-l-ethylpyrrole-2-acetic acid; 5-(p-methylbenzoyl)- l -(n-propyl)pyrrole-2-acetic acid; 5-(p-methoxybenzoyl')-l-ethylpyrrole-Z-acetic acid;

and 5-(2,4-dichlorobenzoyl)-l-(n-butyl)pyrrole-2- acetic acid.

residue crystallized from methanol. The crystals thus obtained are recrystallized from methanol togive lbenzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solid, m.p. l04-l06C.

EXAMPLE XLlX l-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid: A suspension of 3.0 g. (0.009 mole) of l-benzyl-5-(pchlorobenzoyl)-pyrrole-2-acetonitrile in 20 ml. of ethanol and 18 ml. (0.018 mole) of 1N sodium hydroxide is refluxed for 6 hours. The mixture is diluted with water and the ethanol evaporated in vacuo. The solution is washed with chloroform and ether and acidified with 3N hydrochloric acid. The precipitated solid is collected and dried in vacuo to give about 2.8 g. (91 percent yield) of" l-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid as white crystals, M.P. l62l63C.

Analysis: Calcd. for C ,,H CINO C, 67.70; H, 4.56; N, 3.9 79 H 465' N 3.9

Found: C, 67.

EXAMPLE XLVlI EXAMPLE XLVIlI 1-Benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile: A solution of 8.43 ml. (0.0663 mole) of pchlorobenzoyl chloride and 8.8 g. (0.0663 mole) of aluminum chloride in 100 ml. of l,2-dichloroethane is added to 'a solution of 13.0 g. (0.0663 mole) of lbenzylpyrrole-2-acetonitrile in 50 ml. of 1,2- dichloroethane at 5C. over a 5 minute period. The mixture is stirred for 15 minutes and then heated quickly to reflux for 3 minutes. The reaction mixture is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and washed with chloroform. The combined organic solutions are washed lution, dilute hydrochloric acid, and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the oily residue dissolved in benzenemethylcyclohexane and seeded with crystals of lbenzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile.

After crystallization of the latter substance is complete, the mother liquor is filtered and evaporated and the EXAMPLE L The procedure of Example XLVIII is followed to prepare S-aroyl-l-R -pyrrole-2-acetonitriles wherein R is benzyl. For example, by repeating such procedure with an equivalent amount of an appropriate benzoyl chloride in place of the p-chlorobenzoyl chloride used therein, the following respective products are obtained:

l-benzyl-5-benzoyl-pyrrole-2-acetonitrile;

l-benzyl-S p-bromobenzoyl )-pyrrole-2-acetonitrile;

1-benzyl-5-(p-ethoxybenzoyl)-pyrrole-2-acetonitrile;

l-benzyl-5-(2,4-dichlorobenzoyl)-pyrrole-2- acetonitrile; and

l-benzyl-5-(3', acetonitrile.

4-dimethylbenzoyl)-pyrrole-2- EXAMPLE LI A. The nitrile-to-acid transformation procedure of Example XLlX is followed using an equivalent amount of each acetonitrile obtained in Example L to yield, as respective products, the corresponding l-benzyl-S- aroyl-pyrrole-2-acetic acids.

B. Each of the l-benzyl acids obtained from Examples XLlX and Ll-A is heated under reflux for a few hours with an excess of anhydrous methanol in the presence of a trace of dry hydrogen chloride to yield the corresponding methyl esters.

EXAMPLE Lll The alkylation and transformation procedures of Examples XXXIV and XXXV, respectively, are repeated, except that an equivalent amount of an appropriate I- benzyl-S-aroylpyrrole-2-acetonitrile and an equivalent amount of an appropriate alkyl halide as the alkylating agent are used to yield the following respective products:

l-benzyl-5-(p-chlorobenzoyl)-a-methyl-pyrrole-2- acetic acid; l-benzyl-5-benzoyl-a-(n-propyl)-pyrrole-2-acetic acid;

EXAMPLE Llll -(p-Chlorobenzoyl)- l methylpyrrole-Z-acetonitrile: An acylating solution is prepared by the slow addition of 278 g. (1.58 moles) of p-chlorobenzoyl chloride to 210 g. (1.58 moles) of aluminum chloride in 750 ml. of ethylene chloride. The resulting solution is added to a solution of 190 g. (1.58 moles) of N-methylpyrrole-Z- acetonitrile in 750 ml. of ethylene chloride. The temperature is maintained at 20-22C. during the addition; and the solution is further stirred at room temperature for one hour. The solution is then heated rapidly to 74-76C. at which point there is a vigorous evolution of hydrogen chloride gas. This temperature is maintained about 5 minutes and the solution is cooled rapidly and poured into ice water. The product is extracted with methylene chloride and washed with water. The organic solution is then shaken with an excess of an aqueous solution of N,N- dimethylaminopropylamine followed by dilute hydrochloric acid in order to remove any excess pchlorobenzoyl chloride. After a final wash with brine,

.the solution is dried over anhydrous magnesium sulfate.

Distillation of the solvent leaves a residue which crystallizes. Recrystallization from methyl alcohol yields the product, 5-(p-chlorobenzoyl)-l-methylpyrrole-2- acetonitrile, m.p. l20-l24C. After two additional recrystallizations from methanol, the m.p. is l27-l3 1C.

EXAMPLE LIV 5 -(p-Chlorobenzoyl)- l -methylpyrrole-2-acetic acid: A mixture of 129 g. (0.52 mole) of 5-(pchlorobenzoyl)-l-methylpyrrole-2-acetonitrile and 88 g. (1.] moles) of 50 percent sodium hydroxide solution in 800 ml. of ethanol and 500 ml. of water is stirred and refluxed for about 18 hours with slow evolution of ammonia. The solution is then cooled to about 50C. and acidified by adding 1 ml. of concentrated hydrochloric acid. The mixture is cooled and the precipitated product. 5-(p-chlorobenzoyl)-l-methylpyrrole-2- acetic acid, is filtered and recrystallized from methanol, m.p. l93l95C. (dec.). A second crop is obtained upon concentration of the mother liquor for a total yield of about 67 percent of theoretical.

Analysis: Calcd. for C H CINO N, 5.05% Found: N, 5.06%

EXAMPLE LV Ethyl 5-(p-chlorobenzoyl)-1-methyl-pyrrole- 2-acetate: A suspension of 55.4 g. of 5-(ption, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The crystalline residue is recrystallized twice from cyclohexane to give ethyl 5- (p-chlorobenzoyl)-l-methyl-pyrrole-Z-acetate as a yellow solid, m.p. 74-76C.

EXAMPLE LVI The procedure of Example LV is repeated except that an equivalent amount of isopropanol and nbutanol are used in place of the ethanol used therein to yield, as respective products, the corresponding isopropyl and n-butyl esters of 5-(p-chlo robenzoyl)- 1 methylpyrrole-Z-acetate.

EXAMPLE LVll A. Methyl l-methylpyrrole-2-acetate: Four hundred and fifty ml. of ethereal diazomethane [prepared from 43 g. (0.2 mole) of N-methyl-N-nitroso-ptoluenesulfona'mide by the method described in Organic' Synthesis, Vol. IV, John Wiley & Sons, p. 250-252, (1963] is added dropwise to a cooled solution of l8.l g. (0.13 mole) 1-m.ethylpyrrole-2-acetic acid in ml. of anhydrous methanol keeping the temperature at approximately 0C. When the evolution of gas ceases, the mixture is washed three times with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is evaporated, yielding about 14.5 g. of an oily residue of methyl l-methylpyrrole-2-acetate which is used without further purification in the procedure of Example LVlIl-A.

B. Methyl pyrrole-Z-acetate is obtained by repeating the procedure of Example LVIll-A, except that an equivalent quantity of pyrrole-2-acetic acid is used in place of the l-methylpyrrole-2-acetic acid used therein.

EXAMPLE LVIII A. Methyl 5-(p-chlorobenzoyl)-l-methylpyrrole- Z-acetate: Ten and a half grams of p-chlorobenzoyl chloride is added dropwise to a chilled suspension of 8 g. (0.06 mole) of aluminum chloride in 60 ml. of methylene chloride. The resulting solution is added quickly but dropwise to a solution of 7.6 g. (0.05 mole) methyl l-methylpyrrole-2-acetate in 30 ml. of methylene chloride keeping the temperature below 10C. The reaction mixture is stirred for twenty minutes, then poured into 3N hydrochloric acid, and the resulting mixture extracted with ether. The ether fraction is washed successively with N,N-dimethyl-1,3-propanediamine, with 3N hydrochloric acid and with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo and the resulting solid, methyl 5-(p-chlorobenzoyl)-l-methylpyrrole-2-acetate, is purified by recrystallization from methanol, m.p. l22-l25C.

B. Methyl 5-(p-chlorobenzoyl)pyrrole-2-acetate is obtained by repeating the procedure of Example LVlIl- A, except that an equivalent quantity of methyl pyrrole-2-acetate is used in place of the methyl l-methylpyrrole-Z-acetate used therein.

EXAMPLE LIX By repeating the procedures of Example LVlIl (A and B), except that an equivalent quantity of an appropriate benzoyl chloride is used in place of the p product chlorobenzoyl chloride used therein, the following respective products are obtained:

methyl -benzoyl-pyrrole-2-acetate;

methyl 5-benzoyl-1-methylpyrrole-Z-acetate;

methyl 5-( p-bromobenzoyl)- l -rnethylpyrrole- 5 2-acetate; methyl 5-(p-methoxybenzoy1)- l -methylpyrrole- 2-acetate; and methyl 5-(2',4'-dichlorobenzoyl)-pyrrole-2-acetate.

EXAMPLE LX 5-(p-Chlorobenzoyl)-1-methylpyrrole-Z-acetamidez A mixture of 12.4 g. (0.05 mole) of 5-(p- EXAMPLE LX111 5-( p-Chlorobenzoyl)-N,N-diethyll -methylpyrrole- 2-acetamide: To a solution of 6.1 g. (0.02 mole) of 5- (p-chlorobenzoyl)-l-methylpyrrole-2-acetic acid in 100 ml. chloroform is added 3.8 ml. (0.03 mole) thionyl chloride. The mixture is stirred and refluxed overnight. The solvent is then evaporated and the residue is added quickly to a solution of 22 ml. diethylamine in 50 ml. water while cooling externally with an ice-bath. A solid precipitates, S-(p-chlorobenzoyl)-N,N-diethyll-methylpyrrole-2-acetamide, which is collected and purified by recrystallization from methylcyclohexane (with charcoal while in solution), m.p. 8285C.

Analysis: Calcd. for C H CIN O C, 64.

9 Found: C, 65.0

chlorobenzoyl)-l-methylpyrrole-2-acetonitrile and 8 g. of 50 percent sodium hydroxide solution in 50 ml. of water and 75 ml. of methyl alcohol is stirred and refluxed for 45 minutes. The resulting solid is filtered from the hot solution and recrystallized from dimethyl 25 formamide to give about 8.5 g. (62 percent) of the 5-(p-chlorobenzoyl)-l-methylpyrrole-2- acetamide, m.p. 250253C.(dec.).

Analysis: Calcd. for c,,H,,c1N,o,= N, 10.13% Found: N, 9.97%

EXAMPLE LXI The procedure of Example LX is followed to hydrolyze the cyano function of the subject compounds to an amide function (i.e., R For example, by repeating said procedure with an equivalent amount of an appropriate 5-aroyl-l-R -2-alkanonitrile as the starting material, the following respective products are obtained:

S-benzoyl-1-methylpyrrole-2-acetamide;

5-(p-chlorobenzoyl)-pyrrole-2-acetamide;

5-(3 -chloro-p-toluoyl)-1-methylpyrrole-2- acetamide;

S-(p-methoxybenzoyl )-pyrrole-2-acetamide;

5 p-chlorobenzoyl l -ethylpyrrole-Z-acetamide;

and

1 -benzyl-5 -(p-chlorobenzoyl )-pyrrole- 2-acetamide.

EXAMPLE LXll S-(p-Chlorobenzoyl)-N1ethyll -methylpyrrole-2- acetamide: A suspension of 6.0 g. (0.02 mole) of the sodium salt of S-(p-chlorobenzoyl)-l-methylpyrrole-2- acetic acid in 100 ml. of dry benzene is treated with 2.1 ml. (0.025 mole) of oxalyl chloride in 100 ml. benzene. The mixture is stirred for 3 hours, filtered, evaporated in vacuo and the residue taken up in benzene. The benzene mixture is poured into 50 ml. of percent ethylamine in 200 ml. of water. The precipitated solid is filtered and dried. It is recrystallized from ethanol to give about 2.0 g. of S-(p-chlorobenzoyl)-N-ethyl-lmethylpyrrole-2-acetamide as white needles, m.p. 65

EXAMPLE LXlV EXAMPLE LXV the procedure described by R. Jones and J. Lindner in the Canadian Journal of Chemistry, 18, 883 (1965), wherein N-alkylpyrrole-2-carboxaldehydes are reacted with ethoxycarbonylmethylene triphenylphosphorane to yield ethyl 2-(1-alkyl-2-pyrrolyl)-acry1ates, is followed to prepare, as respective products, the l-methyl, l-(n-butyl) and l-isoamyl derivatives of ethyl 2-(2- pyrrolyl)-acrylate.

EXAMPLE LXVl Ethyl 2-( l-methy1-2-pyrrolyl)-propionate: A solution of 62.4 g. (0.35 mole) ethyl 2-(l-methyl-2-pyrrolyl)' acrylate in 350 ml. percent ethanol is hydrogenated in a Parr shaker using 3 g. of platinum oxide as the catalyst. The hydrogenation is continued overnight under 32 p.s.i. of hydrogen. The mixture is filtered and the filtrate concentrated in vacuo. The residual yellow oil is dissolved in ether and washed successively with 3N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ether solution is dried over anhydrous magnesium sulfate. The

Analysis: Calcd. for c,,H,,c|N,o,; C, 63.05; H, 5.62; N, 9. Found: C, 63.06; H, 5.61; N, 9.

EXAMPLE LXVll Ethyl -(p-chlorobenzoyl)-l-methylpyrrole-2- propionate: To a suspension of 26.6 g. (0.2 mole) of aluminum chloride in 100 ml. methylene chloride is added 34.8 g. (0.2 mole) of p-chlorobenzoyl chloride. The resulting solution is added dropwise to a solution of 36.8 g. (0.2 mole) of ethyl 2-(1-methyl-2-pyrrolyl)- propionate in 100 ml. methylene chloride while cooling externally with an ice bath. After the addition is complete, the reaction is stirred for minutes and poured into ice acidified with dilute hydrochloric acid. The two fractions are separated. The organic fraction is washed successively with N,N dimethyl-l,3-propanediamine, 3N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. A solid is crystallized in the resulting oily residue which is isolated and purified by recrystallization from methanol to yield ethyl 5-(p-chlorobenzoyl)-lmethylpyrrole-Z-propionate, m.p. 7 l .5-73C.

EXAMPLE LXVIII EXAMPLE LXIX The successive procedures of Examples LXVI, LXVll and LXVlll are repeated, except that an equivalent amount of the l-(n-butyl) and l-isoamyl derivative of ethyl 2-(2-pyrrolyl)-acrylate is used initially, to yield, as respective products:

ethyl 2-( l-n-butyl-2-pyrrolyl)-propionate;

ethyl 2-( l-isoamyl-2-pyrrolyl)-propionate;

ethyl 5-(p-chlorobenzoyl)- l -n-butylpyrrole-2- propionate;

ethyl 5-( p-chlorobenzoyl l -isoamylpyrrole-2- propionate;

5-(p-chlorobenzoyl)-1-n-butylpyrrole-2-propionic acid; and

5( p-chlorobenzyyl)- l -isoamylpyrrole-2-propionic acid.

EXAMPLE LXX A. The acylation procedure of Example LXVII is repeated, except that an equivalent amount of an appropriate ethyl 2-( l-alkyl-2-pyrrolyl)-propionate and an equivalent amount of an appropriate benzyol chloride acylating agent are employed, to yield as respective products:

ethyl S-(p-methylbenzoyl)-1-methylpyrrole-2- propionate;

ethyl S-(p-ethoxybenzoyl l -n-butylpyrrole2- propionate;

ethyl 5-(2',4'-dichlorobenzoyl)-l-methylpyrrolc-Z- propionate;

ethyl 5-(p-cyanobenz0yl l -isoamylpyrrole-2- propionate;

ethyl S-(p-methylthiobenzoyl)-l-methylpyrrole-2- propionate;

ethyl S-(p-nitrobenzoyl l -methylpyrrole 2- propionate; ethyl 5-(3,45-trimethoxybenzoyl)-1-methylpyrrole-Z-propionate;

ethyl S-thenoyl-l-methylpyrrole-Z-propionate;

ethyl 5-(5-methylthenoyl)-l-methylpyrrole-2- propionate; and

ethyl 5-(p-trifluoromethylbenzoyl)-l-methylpyrrole- 2-propionate.

B. The ester-to-acid transformation procedure of Ex ample LXVlll is repeated using an equivalent amount of each propionate ester obtained from Example LXX-A in place of the ester used therein to yield, as respective products, the corresponding S-aroyl-lalkylpyrrole-Z-propionic acid.

C. By using an equivalent amount of ethyl S-(pnitrobenzoyl)-1-methylpyrrole-2propionate in place of 5-(p-nitrobenzoyl)-l-methylpyrrole-2-acetonitrile in the hydrogenation procedure of Example XXlV, the product, ethyl 5-(p-aminobenzoyl.)-l-methylpyrrole-2- propionate is obtained. Conventional ammonolysis of the latter ester with ammonia or treatment with a primary or secondary lowe alkylamine affords the corresponding propionamides.

D. By repeating the hydrolysis procedure of Example LXVIII with an equivalent amount of the ester obtained from Example LXX-C in place of the ester used therein, the product, 5-(p-aminobenzoyl)-l methylpyrrole-Z-propionic acid is obtained.

EXAMPLE LXXI EXAMPLE LXX" A. Ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate: A solution of 71 g. (0.37 mole) of lphenyl-l,2,3-butanetrione-2-oxime in 350 ml. glacial acetic acid and 50 ml. of water is added to 75.5 g. diethyl acetonedicarboxylate in 350 ml. of glacial acetic acid at C. Concurrently, a mixture of 73 g. (l.l2 mole) of zinc dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added in portions at such a rate that the temperature is maintained near C. After the additions are complete (about 45 minutes), the mixture is refluxed for one hour and poured into iced water. The resulting crude semisolid is collected by filtration and recrystallized twice from methanol to give ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole- ,2-acetate, m.p. l52-154C.

Analysis: Calcd. for C H NO C, 66.46; H, 6.16; N, 4.08% Found: C, 66.50; H, 6.20, N, 4.l7%

B. By repeating the procedure of Example LXXll-A with an equivalent amount of the l-p-chlorophenyl, lp-methylphenyl and l-p-methoxyphenyl derivative of l,2,3-butanetrione-2-oxime, there are obtained as respective products, the corresponding ethyl -aroyl-3- ethoxycarbonyl-4-methylpyrrole-Z-acetates.

EXAMPLE LXXlll A. 5-Benzyol-3-carboxy-4-methylpyrrole-2-acetic acid: A mixture of 3.4 g. of ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, g. of 50 percent sodium hydroxide solution and 10 ml. of water is refluxed for 2 hours. The reaction mixture is then diluted with water and acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, air-dried, and recrystallized from acetone-water to yield the product, 5-benzoyl-3-carboxy-4-methylpyrrole-2-acetic acid, as white crystals, m.p. 250-253C.

B. The hydrolysis procedure of Example LXXlll-A is repeated, except that an equivalent amount of each ester obtained in Example LXXll-B is used, to yield, as respective products, the corresponding S-pchlorobenzoyl, S-p-methylbenzoyl and 5-pmethoxybenzoyl derivatives of 3-carboxy-4-methylpyrrole-2-acetic acid.

EXAMPLE LXXlV EXAMPLE LXXV A. 5-Benzoyl-4-methylpyrrole-2-acetic acid: A solution of 4.13 g. (0.0l3l mole) of ethyl 5-benzoyl-3- carboxy-4-methylpyrrole-2-acetate in 80 ml. of quinoline in the presence of a trace amount of copper chromite is heated at l80l 83C. for 5 hours. The mixture is poured into dilute hydrochloric acid and extracted three times with ether. The ether extracts are combined and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give about 4 g. of semisolid ethyl 5-benzoyl-4-methylpyrrole-2-acetate which is.

used in the following hydrolysis procedure without further purification.

The entire semisolid is dissolved in ml. of ethanol and 20 ml. of 1N sodium hydroxide solution is added. The mixture is heated under reflux for minutes. The solvent is then evaporated in vacuo and the residue dissolved in water and washed with ether. The aqueous solution is acidified with dilute hydrochloric acid and the resulting crystalline solid (1.6 g., 50 percent yield) is collected by filtration and air-dried. The product, 5- benzoyl-4-methylpyrrole-Z-acetic acid, is recrystallized three times from acetone-water with charcoaling, m.p. l67-l68C.

B. The procedure of Example LXXV-A is repeated using an equivalent amount of the respective esters obtained in Example LXXlV-B to yield the corresponding S-p-chlorobenzoy], S-p-methylbenzoyl and 5-pmethoxoybenzoyl derivatives, respectively, of 4-methylpyrrole-2-acetic acid.

C. Lower alkyl esters of the acids obtained in A and B of this Example, such as, for example, theethyl, isopropyl and n-butyl esters, are prepared by conventional esterification techniques using an appropriate lower alkanol.

D. Primary, secondary and tertiary amides of the acids obtained in A and B of this Example are prepared by conventional procedures, for example, by treatment with thionyl chloride and then contacting the thusobtained acid chloride with ammonia, a primary lower alkylamine or a secondary lower alkyla mine, such as:

S-benzoyl-N,N-diethyl-4-methylpyrrole-2- acetamide; 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetamide; 5-(p-methylbenzoyl)-N-methyl-4-methylpyrrole-2- acetamide; and V S-(p-methoxybenzoyl)-N-ethyl-4-methylpyrrole-2- acetamide.

EXAMPLE LXXVI A. Ethyl 5-(p-chlorobenzoyl)-2,4-dimethylpyrrole- 3-acetate: To a solution of'29 g. (0.17 mole) of pchlorobenzoyl chloride and 28.0 g. (0.15 mole) of ethyl 2,4-dimethylpyrrole-3-acetate in ml. carbon disulfide, is added 41.23 g. (0.31 mole) of anhydrous aluminum chloride. The reaction mixture is cooled externally with an ice bath. The mixture is stirred for 15 minutes after which the solvent is decanted and the remaining solid treated with ice acidified with 3N hydrochloric acid. The acidic mixture is extracted three times with ether. The combined ether extracts are washed successively with N,N-dimethyl-],3-propanediamine, 3N hydrochloric acid, and a saturated solution of sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The remaining solid is recyrstallized from methanol to yield, ethyl S-(p-chlorobenzoyl)-2,4-dimethylpyrrole-3-acetate, m.p. l26-129C.

B. By repeating the procedure of Example LXXVl-A, except that an equivalent amount of an appropriate benzoyl chloride is used as the acylating agent, there are obtained as respective products:

ethyl 5-benzoyl-2,4-dimethylpyrrole-3-acetate;

ethyl S-(p-methoxybenzoyU-Z,4-dimethylpyrrole- 3-acetate;

ethyl 5-(2',4'-dichlorobenzoyl)-2,4-dimethylpyrrole- 3-acetate;

ethyl 5-(3-chloro-4'-methylbenzoyl)-2,4-dimethylpyrrole-3-acetate A. Ethyl -(p-chlorobenzoyl)-4-methyl-2- trichlormemthylpyrrole-3-acetate: To a suspension of 9.6 g. (0.03 mole) of ethyl 5-(p-chlorobenzoyl)-2,4- dimethylpyrrole-3-acetate in 75 ml. ether is added dropwise 7.8 ml. sulfurylchloride, cooling externally with an ice bath. The resulting suspension is stirred at room temperature for hours. The resulting white solid, ethyl 5-(p-chlorobenzoyl)-4-methy1-2- trichloromethylpyrrole-3-acetate, is filtered and purified by recrystallization twice from methylcyclohexane, m.p. 133-l37C.

B. Perchlorination of the Z-methyl group in the esters obtained from Example LXXVI-B is performed by repeating the procedure of Example LXXVll-A.

EXAMPLE LXXVlll A. 5-(p-Chlorobenzoyl)-4-methyl2-carboxypyrrole- 3-acetic acid: A solution of 1.0 g. (0.0026 mole) of ethyl S-(p-chlorobenzoyl)-4-methyl-2-trichloromethylpyrrole-3acetate in 10 ml. dioxane and 3 ml. water is refluxed for three hours. The resulting solution is cooled and extracted with chloroform. The organic fraction is extracted with saturated solution of sodium bicarbonate. The aqueous phase is made acidic with dilute hydrochloric acid and the resulting precipitate of 5-(p-chlorobenzoyl)-4-methyl-2-carboxypyrrole-3- acetic acid is filtered and dried, m.p. 240C.

B. The procedure of Example LXXVIII-A is repeated using an equivalent amount of the 2-trichloromethyl esters obtained from Example LXXVII-B to yield, as respective products, the corresponding 5-aroyl-4- methyl-2-carboxypyrrole-3-acetic acids.

EXAMPLE LXXIX A. 5-(P-Chlorobenzoyl)-4-methylpyrrole-3-acetic acid: A solution of 1.4 g. (0.004 mole) of S-(pchlorobenzoyl)-4-methyl-2-carboxypyrrole-3-acetic acid in ml. quinoline is heated overnight at 160C. under nitrogen. The reaction is poured into ice acidified with hydrochloric acid. The mixture is extracted with chloroform and the organic phase is extracted with a saturated solution of sodium bicarbonate. The basic solution is made acidic with dilute hydrochloric acid and the resulting solid, 5-(p-chlorobenzoyl)-4- methylpyrrole-3-acetic acid, is filtered and purified by recrystallization from isopropyl alcohol, m.p. l45-l47C.

B. The decarboxylation procedure of Example LXXlX-A is repeated, except that an equivalent amount of the 2-carboxypyrrole-3-acetic acids obtained in Example LXXVIII-B is used as the starting acid, to yield the corresponding 5-aroyl-4-methylpyrrole-3-acetic acids, respectively.

C. Lower alkyl esters of the acids obtained in A and B of this Example, such as, for example, the ethyl, isopropyl and n-butyl esters, are prepared by conventional esterification procedures using an appropriate lower alkanol.

D. Primary, secondary and tertiary amides of the acids obtained in A and B of this Example are prepared by conventional procedures to yield, for example, the following respective amides:

5(p-chlorobenzoyl)-4-methylpyrrole-3-acetamide;

S-benzoyl-N-ethyl-4-methylpyrrole-3-acetamide;

5-(p-methoxybenzoyl)-N-n-propyl-4-methylpyrrole- 3-acetamide;

38 5-(2,4' dichlorobenzoyl )-N,N-diethyl-4-methylpyrrole-3-acetamide EXAMPLE LXXX A. Z-Dimethylaminomethyl-l-benzylpyrrole: A solution of 8.2 g. (0.1 mole) dimethylamine hydrochloride in 8 ml. formalin is added dropwise to 17.12 g. (0.1 mole) of l-benzylpyrrole. The mixture is stirred at room temperature until solution occurs (about 4 hours). The solution is poured into 10 percent sodium hydroxide solution and then extracted into ether three times. The combined organic fractions are washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent evaporated in vacuo. The product, 2-dim.ethylaminomethyllbenzylpyrrole, is distilled at reduced pressure. b.p. 72C., 0.025 mm. Hg.

B. 2-Dimethylaminomethyl-l-benzylpyrrole methiodide: A solution of 100 g. (0.47 mole) of 2- dimethylaminomethyl-l-benzylpyrrole in 200 ml. of absolute ethanol is cooled to 5C. To this is added dropwise 29.4 ml. (0.47 mole) of methyl iodide. A white solid precipitates. The suspension is stirred until the precipitate is so thick that additional stirring be comes impossible. The solid, 2-dimethylaminomethyll-benzylpyrrole methiodide, is filtered off and dried in vacuum.

C. 1-Benzylpyrrole-2-acetonitrile: A suspension of 88.9 g. (0.25 mole) of 2-dimethylaminomethyl-lbenzylpyrrole methiodide is added to a suspension of 12.8 g. (0.26 mole) of sodium cyanide in 40 ml. dimethylsulfoxide. The mixture is heated under reflux for 3 hours and stirring at room termperature is continued overnight. The reaction mixture is poured into water and extracted three times with ether. The combined ether extracts are washed with brine and dried over anhydrous magnesium sulfate. The ether solvent is evaporated in vacuo to give about 41 g. of an oily residue which crystallizes upon standing. Recrystallization from methylcyclohexane yields the product, 1- benzylpyrrole-2-acetonitrile, m.p. 62-63C.

EXAMPLE LXXXI A. 3-Chloro-4-methylbenzoyl chloride is prepared by refluxing together 30 g. (0.175 mole) of 3-chloro-4- methyl benzoic acid and 85m]. thinoyl chloride for about 2.5 hours, after which the excess thionyl chloride is distilled off under vacuum. The aroyl chloride product, 3-chloro-4-methylbenzoyl chloride, distills over at b.p. -74C., 10.25 mm. Hg.

B. The procedure of Example LXXXl-A represents a method for transforming benzoic acid derivatives to the corresponding acid chloride form. By following such procedure, except that an equivalent amount of an appropriately substituted benzoic acid is initially employed, the following aroyl chlorides are obtained:

3,4-dimethoxybenxoyl chloride;

3-bromo-4-chlorobenzoyl chloride; 2,3,5-tribromobenzoyl chloride; 3,4-dimethylbenzoyl chloride;

p-ethylbenzoyl chloride;

p-ethoxybenzoyl chloride; and

p-methylthiobenzoyl chloride. 

1. THE PROCESS OF MAKING A LOWER ALKYL 1,4-DILOWERALKYL-3LOWERALKOXYCARBONYL-PYRROLE-2-ACETATE OF THE FORMULA:
 2. The process of claim 1 wherein said dicarboxylate is diethyl acetone dicarboxylate.
 3. The process of claim 1 wherein said dicarboxylate is diethyl acetone dicarboxylate and said loweralkylamine is methylamine.
 4. The process of claim 1 wherein said dicarboxylate is diethyl acetone dicarboxylate, said loweralkylamine is methylamine and said ketone is 1-chloro-2-butanone.
 5. The process of claim 1 wherein said dicarboxylate is diethyl acetone dicarboxylate, said loweralkylamine is methylamine and said ketone is chloroacetone. 